Food allergy, an aberration of oral tolerance, occurs in 6% of children and 3.5% of adults in the United States. Peanut allergy is one of the most common food allergies; most children develop this allergy early in life, do not outgrow it and are at risk for severe and life-ending anaphylactic reactions. Currently there is not a proactive treatment for peanut allergy but we along with others are developing specific types of immunotherapy that will cause these patients to be no longer allergic to peanuts. The significance of this proposal is based on our landmark studies that have examined the effects of peanut oral immunotherapy (OIT) showing a substantial increase in the amount of peanut that a peanut allergic patient can ingest while on therapy (desensitization) and in some cases causing long-term clinical tolerance when the therapy is discontinued. We have identified initial changes in basophil/mast cell reactivity, antigen-specific T cell responses and systemic humoral immune responses in these subjects. Our hypothesis is that peanut OIT will alter the early signaling pathways of basophils/mast cells causing clinical desensitization and then clinical tolerance will develop because of the interrelated changes in allergen-specific T- and B-cells. The long-term goal of this proposal is to better understand the mechanism of the development of oral tolerance to foods in young children treated with allergen immunotherapy. To accomplish this goal our specific aims are the following: Aim 1: Determine the mechanism(s) by which OIT induces hyporesponsiveness in basophils/mast cells in peanut allergic subjects on peanut OIT, Aim 2: Determine the peanut allergen-specific CD4+ T cell frequencies and phenotypes, as well as the suppressive function of Treg cells, that are associated with the development of clinical tolerance to peanuts, Aim 3: Determine the effect of peanut-specific mucosal and systemic humoral immune responses in OIT on clinical tolerance. The studies will help us identify the mechanism and durability of the desensitized state and then the development of tolerance to foods after OIT. A treatment for peanut allergy is critically needed, the completion of these studies will provide a strong scientific basis for the development of OIT and other types of therapy that hope to produce long-term clinical tolerance to peanuts and other foods. PUBLIC HEALTH RELEVANCE: Food allergy, an aberration of oral tolerance, occurs in 6% of children and 3.5% of adults in the United States. Peanut allergy is one of the most common food allergies; most children develop this allergy early in life, do not outgrow it and are at risk for severe and life-ending anaphylactic reactions. Currently there is not a proactive treatment for peanut allergy but we along with others are developing specific types of immunotherapy that will cause these patients to be no longer allergic to peanuts. The significance of this proposal is based on our landmark studies that have examined the effects of peanut OIT showing a substantial increase in the amount of peanut that a peanut allergic patient can ingest while on therapy (desensitization) and in some cases causing long-term clinical tolerance when the therapy is discontinued. The long- term goal of this proposal is to better understand the mechanism of the development of oral tolerance to foods in young children treated with allergen immunotherapy. .